HIF1 inhibition targets tumoral and myeloid cells, and is a promising therapy for metastatic castration-resistant prostate cancer.

Metastatic prostate cancer (PCa) remains lethal due to limited effective therapies. PTEN and TP53 are commonly mutated tumor suppressors in metastatic PCa, yet the molecular and cellular mechanisms driving aggressiveness and treatment resistance are not fully understood. We have previously shown that mice with both Pten and Trp53 inactivation in prostate luminal cells at adulthood develop aggressive intraductal prostate carcinoma (IDC) and liver metastases. By combining single-cell and spatial transcriptomics, along with flow cytometry and immunohistochemical analyses, we now reveal that prostatic tumors of such mice are hypoxic and progress within a complex immune microenvironment, including neutrophils, TREM2⁺ macrophages, and CCR2⁺ myeloid cells. Moreover, we uncovered that genetic Hif1a inactivation in prostate luminal cells or pharmacological inhibition of HIF1 signaling in Pten/Trp53(i)pe-/- mice does not prevent IDC formation or epithelial plasticity driven by Trp53 loss, but impairs neutrophil recruitment. In addition, HIF1 inhibition reduces CCR2⁺ myeloid cell infiltration. Importantly, targeting these immune cells sensitizes tumors to androgen deprivation and reduces the size of liver metastatic niches. Moreover, pharmacological HIF1 inhibition not only overcomes castration resistance, but also eliminates metastatic niches, offering a more effective approach than direct myeloid cell blockade. Thus, HIF1 targeting emerges as a promising therapy for metastatic castration-resistant PCa.